Protein and Peptide Delivery through Respiratory Pathway - Challenges in Delivery of Therapeutic Genomics and Proteomics - page 429

9.3.1.4 Mucociliary Transport and Alveolar Clearance
Mucociliary clearance and alveolar clearance are the lung's primary defense mecha-
nisms. Particles deposited in the ciliated airways are cleared out by the mucocili-
ary escalator usually within 24-48 h [1,2] . However, particles deposited beyond the
ciliated airways are cleared out by alveolar macrophages [3,4] at a much slower rate
which may take months to years. The drug retention time for the respiratory sys-
tem is primarily determined by the site of initial deposition of drug particles within
the lung and the solubility of inhaled substances for both topical and systemic drug
delivery. Particle size up to 23 m diameter can be phagocytized, but this occurs to
a lesser extent for particles smaller or larger than 3 m diameter [5,6] . Particles less
than 0.1 m are often not recognized by the macrophages.
9.3.2 Biophysics of Inhaled Drug Particles
The pulmonary route is preferred for protein and peptide delivery over conventional
oral delivery because of the absence of metabolizing enzymes in the respiratory sys-
tem. It has been shown that higher bioavailability was achieved by pulmonary admin-
istration of leuprolide acetate than by the oral route [7] . For systemic administrations
of the peptide drugs, an understanding of the physical processes involved in drug
deposition in the respiratory tract from the aerosolized particles is necessary.
9.3.2.1 Geometric Characteristics of the Pulmonary System
To understand drug-particle deposition, one has to understand the dimensions, shape,
and structure of all the parts of the respiratory system (nose, nasopharynx, pharynx,
buccal cavity, oropharynx, larynx, trachea, and bronchial tree).
9.3.2.2 Particle Characteristics Relevant to Pulmonary Drug Delivery
The behavior of the particle during deposition in normal inspiration-expiration cycle
is the special case than the behavior of the particle in general gas-flow streams.
Different summaries were given by Flagan and Seinfield, Byron, Clark, and Pavia.
9.3.3 Critical Factors for Determining Particle Deposition in Lungs
Particle deposition is determined by major factors like inspiration-expiration rate,
particle size, and size distribution. The most important factor for the improvement of
aerosol delivery is the patient. Differences in physiology, such as breathing pattern,
tidal volume, and tracheal inspiration velocity play an important role in this process.
Particle shape and surface morphology are principal factors for consideration in
pulmonary drug delivery, so it is important to assume a particle size in the range of
1-10 m for the effective lung deposition.
9.3.4 Chemical and Physical Properties of Peptide and Protein Drugs
Proteins and peptides are distinguished from drug molecules by virtue of their natu-
ral existence and their building units. Proteins and peptides are made up of amino